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Perinatal Epigenetic Signature of Autism Spectrum Disorder

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Autism Spectrum Disorder (ASD) is a polygenic neurodevelopmental disorder that includes deficits in social communication and repetitive behaviors. Most ASD cases are thought to arise from complex genetics interacting with perinatal environmental factors, complicating the discovery of common genetic risk. The prenatal period is a critical window for neurodevelopment. Environmental factors, especially prenatal nutrients in one-carbon metabolites are crucial for neurodevelopment and provide methyl donors for downstream epigenetic pathways. The epigenetic layer of DNA methylation in placenta reflects developmental and molecular memory of in utero experiences. Placenta, a fetal tissue usually discarded a birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child.

This dissertation details recent progress in understanding the interface of epigenetics, genetics, and environment in ASD etiology. The perinatal epigenomic signature of ASD was investigated by whole-genome-bisulfite sequencing (WGBS) on placenta. First, a pilot study of all male placenta samples from a prospective study MARBLES identified 400 differential methylated regions (DMRs) distinguishing ASD diagnosis. ASD DMRs were significantly enriched at promoters of genes with functions in neuronal development and that overlapped with brain ASD DMRs and known ASD risk genes. Two DMRs at CYP2E1 and IRS2 reached genome-wide significant with methylation level separately affected by genotype, or periconceptional maternal prenatal vitamin use. This pilot study demonstrated that DNA methylation changes in placenta are relevant to brain development and may serve as early epigenetic markers for ASD at birth.

Second, maternal blood samples collected during pregnancy were examined for genome-wide transcriptional signatures of child outcome and nutritional metabolites of one-carbon metabolism. Six transcripts were associated with child outcomes at genome-wide significance, and 1,912 differentially expressed genes with nominal confidence overlapped with known ASD risk genes. A coexpression module enriched in genes with DNA methylation functions showed a suggestive protective association with folic acid and ASD risk. These results demonstrated that the prenatal maternal blood transcriptome is an indicator of gestational nutrition and child neurodevelopment.

Lastly, a multi-cohort and multi-tiered study was performed to integrate genomics, epigenomics, and transcriptomics in placenta and brain, leading to the discovery and functional characterization of a previously uncharacterized novel ASD risk gene NHIP located in a comethylated block at 22q13.33. NHIP was highly expressed in brain, and was induced following neuronal differentiation or hypoxia. Transient NHIP overexpression increased cellular proliferation and altered transcriptome levels in synapses, neurogenesis, and response to oxidative stress. A nearby structural variant was significantly associated with ASD, NHIP expression, and DNA hypomethylation at 22q13.33. Together, these studies identified a novel ASD risk gene related to oxidative stress during brain development that was altered by both common genetic and environmental factors.

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This item is under embargo until August 10, 2023.